The Deubiquitinating Enzyme Ataxin-3 Regulates Ciliogenesis and Phagocytosis in the Retina

Expansion of a CAG repeat in ATXN3 causes the dominant polyglutamine disease spinocerebellar ataxia type 3 (SCA3), yet the physiological role of ATXN3 remains unclear. Here, we focus on unveiling the function of Ataxin-3 (ATXN3) in the retina, a neurological organ amenable to morphological and physiological studies. Depletion of Atxn3 in zebrafish and mice causes morphological and functional retinal alterations and, more precisely, photoreceptor cilium and outer segment elongation, cone opsin mislocalization, and cone hyperexcitation. ATXN3 localizes at the basal body and axoneme of the cilium, supporting its role in regulating ciliary length. Abrogation of Atxn3 expression causes decreased levels of the regulatory protein KEAP1 in the retina and delayed phagosome maturation in the retinal pigment epithelium. We propose that ATXN3 regulates two relevant biological processes in the retina, namely, ciliogenesis and phagocytosis, by modulating microtubule polymerization and microtubule-dependent retrograde transport, thus positing ATXN3 as a causative or modifier gene in retinal/macular dystrophies. [Display omitted] •Atxn3-depleted zebrafish and mice show elongated photoreceptor outer segments•Atxn3 ablation causes mislocalization of cone opsins and cone hyperexcitation•ATXN3 regulates cilium length and ciliary retrograde transport•ATXN3 controls cytoskeleton organization and phagocytosis in RPE cells Toulis et al. show that depletion of Atxn3 causes retinal morphological and electrophysiological alterations, as well as diminished phagocytosis in vivo and in vitro. ATXN3 regulates retinal ciliogenesis and phagocytosis through the KEAP1-SQSTM1-HDAC6-acetylated tubulin pathway by modulating microtubule polymerization and microtubule-dependent retrograde transport.